The N-heterocyclic phosphine (NHP), a five-membered nitrogen containing heterocycle with a unit of —N—P(X)—N— (two P—N bonds and one P—X bond) (Ansell and Wills (2002) Chem. Soc. Rev. 31: 259; Zijp et al. (2005) Dalton Trans. 512; Chelucci et al. (2003) Tetrahedron 59: 9471), has emerged as a powerful synthetic tool in chemical synthesis since its first observation in 1964 (Scherer and Schmidt (1964) Angew. Chem. 76, 787). Traditional NHP-mediated reactions have contributed to both C—C and C—P bond-forming techniques because the focus on NHP chemistry has so far been predominantly directed to phosphorus-donor nucleophiles (Ansell and Wills (2002) Chem. Soc. Rev. 31: 259) that assist NHP in coordinating to metal complexes or in forming covalent bonds to electrophiles as ligands or auxiliaries. For example, chiral and achiral NHP ligands have been utilized to create C—C bonds in various transition metal-catalyzed transformations such as hydroformylation (Breeden et al. (2000) Angew. Chem. Int. Ed. 39: 4106), Heck reactions (Wucher et al. (2011) PNAS 108: 8955), cross-coupling reactions (Ackermann et al. (2010) Org. Lett. 12: 1004), and allylic substitutions (Brunel et al. (1997) Tetrahedron Lett. 38: 5971).
In addition, chiral NHP-oxides of phosphorus-stabilized anions have been successfully employed as auxiliaries for stereoselective Pudovik-type reaction (De la Cruz et al. (1998) Tetrahedron 54: 10513; Blazis et al. (1995) J. Org. Chem. 60: 931) and Michael-type reaction (Hanessian et al. (2000) J. Org. Chem. 65: 5623; Hua et al. (1987) J. Am. Chem. Soc. 109: 5026; Denmark and Kim (1995) J. Org. Chem. 60: 7535) to form a C—P bond providing a stereogenic center to the NHP motifs. The widely known C—P bond forming Michaelis-Arbuzov reaction (Bhattacharya and Thyagarajan (1981) Chem. Rev. 81: 415; Arbuzov (1964) Pure Appl. Chem. 9: 307) utilizes a trialkyl phosphite P(III) and alkyl halide to access dialkyl alkylphosphonates P(V) via an elegant SN2 reaction sequence (Fernandez-Valle et al. (2015) J. Org. Chem. 80: 799; Buck and Yoke (1962) J. Org. Chem. 27: 3675). Since its discovery in 1898 (Michaelis and Kaehne (1898) Ber. Dtsch. Chem. Ges. 31: 1048), the Michaelis-Arbuzov reaction has served as a standard protocol for forming C—P bonds in versatile phosphonate derivatives such as phosphinate and phosphine oxide. Synthesis of such compounds, however, requires the use of aliphatic halides possessing good leaving groups and high temperature. Thus, for the search of more general and mild reaction conditions, attempts to expand the scope of the substrates within sp2 carbon-containing electrophiles were demonstrated by Perkow (Borowitz et al. (1972) J. Am. Chem. Soc. 94: 1623) and Dougherty (Kedrowski and Dougherty (2010) Org. Lett. 12:3990). Alternatively, efforts of seeking mild reaction conditions resulted in the finding of Lewis acid-mediated reactions (Rajeshwaran et al. (2011) Org. Lett. 13: 1270; Renard et al. (2003) Angew. Chem. Int. Ed. 42: 2389).
Despite the widespread utility of NHPs, there remains limitations in terms of the substrate scope, only sp3- or sp2-carbon-containing electrophiles are tolerated, and reaction temperature, which increases the chance of side reaction (Fernandez et al. (2015) J. Org. Chem. 80: 799). These needs and others are met by the present invention.